JPS61282366A - Imidazole derivative - Google Patents

Abstract

NEW MATERIAL:An imidazole derivative expressed by formula I (X is halogen, lower alkyl or lower alkoxy; R is H or lower alkyl, provided that R is lower alkyl when X is lower alkyl) or a salt and/or hydrate thereof. EXAMPLE:4-[ alpha-Hydroxy-2-methoxy-5-(1-imidazolyl)benzyl ]-3,5-dimethylbe nxoic acid. USE:With pharmacological action, e.g. inhibitory action on biosynthesis of thromboxane A2, inhibitory action on blood platelet agglutination, etc., effective as a preventing and treating agent for thrombosis, cerebral apoplexy, myocardial infarction, acute cardiac death, angina pectoris, hypertension, asthma, nephritis, etc., and further as an agent useful for preventing metastasis of cancer and orally administrable. PREPARATION:For example, a compound expressed by formula II is suspended or dissolved in a solvent, e.g. water or methano, and reacted with a metal hydride complex compound, e.g. sodium born hydride, at room temperature - 100 deg.C to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to novel and pharmaceutically useful imidazole derivatives or pharmaceutically acceptable salts and/or hydrates thereof.

[Conventional technology]

JP-A-58-150566 discloses that thromboxane A2 has pharmacological effects such as inhibition of biosynthesis, inhibition of platelet aggregation, and vasodilation, and is effective against thrombosis, stroke, myocardial infarction, acute cardiac death, and angina. It describes imidazole derivatives or acid addition salts thereof that are useful for the prevention and treatment of diseases such as hypertension, hypertension, asthma, and nephritis.

Among the compounds disclosed in this published patent application publication,
The one with the best pharmacological action is α−(
2,4,6-drimethylphenyl)-2-methyl-5-
It was (1-imidazolyl) benzene methanol (hereinafter also referred to as the compound to Ni). (The Japan
esae Journal ofPharn+aco1
ogy+ Volume 36 (Supplement) Page 226 (1984)].

[Problem that the invention seeks to solve]

However, this compound has been found to inhibit hepatic drug-metabolizing enzymes, resulting in unfavorable effects such as induction of drug-metabolizing enzymes and liver hypertrophy, and its inhibition of thromboxane biosynthesis is not very strong. It has become clear that this is not necessarily a satisfactory preventive or therapeutic agent for the various diseases mentioned above.

[Means for solving problems]

Therefore, the present inventors conducted intensive studies to find a compound that is effective and has fewer side effects as described above, and as a result, it was found that a compound that is not specifically described as an example in the above publication has an excellent effect and It was discovered that the side effects were weak, and the present invention was completed. That is, the present invention relates to an imidazole derivative represented by the general formula or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.

In the formula, X represents halogen, lower alkyl, or lower alkoxy, and R represents hydrogen or lower alkyl. However, when X represents lower alkyl, R represents lower alkyl.

Halogen refers to chlorine, bromine, fluorine, and iodine; lower alkyl refers to alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl; lower alkoxy refers to methoxy and ethoxy. , propoxy, isopropoxy, butoxy, isobutoxy,
It means alkoxy having 1 to 4 carbon atoms such as tertiary butoxy.

The compound of general formula (1) of the present invention is produced, for example, by the following method.

A method for reducing a compound represented by the general formula (wherein X and R have the same meanings as above).

This reaction is carried out in a suitable solvent (water, methanol, ethanol, dioxane or a mixed solvent thereof) using the general formula (I
The compound [) is suspended or dissolved and mixed with a metal hydrogen complex compound such as sodium borohydride at around room temperature to around the boiling point of the solvent, more preferably at room temperature to 100°C, for 1 to 100°C.
It takes place over a period of 24 hours.

Additionally, this reaction can be carried out using a suitable non-aqueous solvent (diethyl ether, tetrahydrofuran, dioxane, benzene, etc.).
Among these, the reaction is carried out with a metal hydrogen complex compound such as lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride at a temperature ranging from around room temperature to around the boiling point of the solvent.

Imidazole and the general formula (in the formula, Y represents chlorine, bromine, iodine, fluorine,
R has the same meaning as above. ), preferably in the presence of a base.

The reaction is carried out using sodium hydride, potassium carbonate, sodium carbonate, hydroxide, etc. in an appropriate solvent (benzene, toluene, nitrobenzene, dimethylformamide, hexamethylphosphorotriamide, isoamyl alcohol, N-methylpyrrolidone, etc., or a mixed solvent thereof). in the presence of an inorganic base such as sodium and an organic base such as triethylamine at temperatures ranging from room temperature to the boiling point of the solvent used.
It will progress in 48 hours. In addition, copper powder and iodide are used as catalysts.
The reaction proceeds more smoothly when copper, potassium fluoride, etc. are used.

When X and R are both lower alkyl, it can be easily synthesized by esterifying a compound represented by the general formula % (wherein X' represents lower alkyl) by a conventional method. That is, the corresponding ester can be easily obtained by carrying out the reaction in methanol, ethanol, or isopropanol using an acidic catalyst such as hydrochloric acid or sulfuric acid or a basic catalyst such as sodium methylate or sodium ethylate.

It is also convenient to react (synthesize) a salt of compound (IV) (a metal salt such as a sodium salt or a potassium salt, or an organic salt such as triethylamine) with an alkyl halide or an alkyl sulfuric acid. Depending on the situation, solvents such as dimethylformamide, dimethylsulfoxide, toluene, acetone, alcohol, etc. are used.Furthermore, in the case of methyl esters, esterification with diazomethane is also a very common technique.

The imidazole derivative of the general formula (1) produced in this manner may be treated with an inorganic acid such as hydrochloric acid, hydrobromic acid, or sulfuric acid, and an inorganic acid such as fumaric acid, maleic acid, mandelic acid, citric acid, tartaric acid, or salicylic acid. It can be an acid addition salt with an organic acid, a salt with a metal such as sodium, potassium, calcium, magnesium, or aluminum, or a salt with an amino acid such as lysine.

The compound of the present invention has optical isomers, and the present invention includes both these individual isomers and mixtures thereof. If it is necessary to resolve a racemic compound, known means such as fractional crystallization and various chromatography techniques can be used.

Compounds (II), (nI), and (IV), which are raw materials, are new compounds and are produced, for example, as follows.

general formula (In the formula, Z represents isopropyl or acetyl, and X.

Y has the same meaning as above. ) By reacting the compound represented by the general formula (wherein X and Y are the same as above) with imidazole (carrying out an esterification reaction as appropriate), which is obtained by oxidizing the compound represented by Compound (II) is obtained.

Compound (II) is obtained by reducing compound (IV) (performing an appropriate esterification reaction), and compound (I
V) is obtained by reacting compound (I[[), which is a carboxylic acid compound, with imidazole.

[Action and effect of the invention]

Imidazole derivatives of general formula (I) and their pharmaceutically acceptable salts and/or hydrates have pharmacological effects such as inhibiting the biosynthesis of thromboxane A2 and inhibiting platelet aggregation, leading to thrombosis and stroke. It is useful for the prevention and treatment of myocardial infarction, acute cardiac death, angina pectoris, hypertension, asthma, nephritis, ischemic cerebral circulation disorder, and the prevention of cancer metastasis.

When used as a medicine, the compound of the present invention can be administered orally by itself or mixed with appropriate pharmacologically acceptable carriers, excipients, diluents, etc. in the form of powder, granules, tablets, capsules, injections, etc. Or it can be administered parenterally.

Although the dosage may vary depending on the target disease and symptoms, it is preferably in the range of 0.01 to 50 μ/day per human body weight ib.

〔Example〕

The present invention will be described in more detail with reference to Reference Examples and Examples below, but the present invention is not limited thereto.

Reference example 1 2.2°, 6°-trimethyl-5-iodo-4”-
Oxidize isopropyl benzophenone with nitric acid, potassium permanganate, potassium dichromate, etc. or 2.2'
, 6'-)dimethyl-5-iodo-4'-acetylbenzophenone to give 4-(2-methyl-5-codebenzoyl)-3,5-dimethylbenzoic acid.

By reducing this with a metal hydrogen complex such as sodium borohydride, the corresponding alcohol, 4-
(α-hydroxy-2-methyl-5-iodobenzyl)
-3,5-dimethylbenzoic acid is obtained.

Reference example 2 4-(2-methyl-5-iodobenzoyl)-3,5-
Dimethylbenzoic acid 53.7 g, imidazole 13.9
g, potassium carbonate 38 g and dimethylformamide 2
1.1 g of potassium fluoride in a suspension of 15 ml
Then, 1.1 g of copper powder was added thereto, and the reaction was carried out at 135° C. for 24 hours with stirring. After cooling, add 430 ml of water, and further add 1.2 g of sodium sulfide 3-elongate.
Continue stirring for a minute.

The precipitated copper sulfide was filtered off under reduced pressure using Celite, the pH of the filtrate was adjusted to 4 with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration.
Dry after washing with water. When this is recrystallized from dimethylformamide, 4-[2-methyl-5-
(1-Imidazolybenzoyl)-3,5-dimethylbenzoic acid can be obtained in almost quantitative yield.

Melting point 252-255°C.

Similarly, 4-[2-methoxy-5-ci-imidazolyl)benzoyl)-3,5-dimethylbenzoic acid (melting point 274-276°C) is obtained.

Reference Example 3 4-[2-Methyl-5-(1-imidazolyl)benzoyl)-3,5-dimethylan,! , 16.2 g of aromatic acid and 2.1 g of sodium hydroxide were dissolved in 113 ml of water, and 2.8 g of sodium borohydride was added thereto to give a solution of 70 to 75 g.
The reaction is carried out under stirring at .degree. C. for 3 hours.

After the reaction, a small amount of insoluble matter was filtered off while still warm, and the filtrate was diluted with
The pH is adjusted to 4 with concentrated hydrochloric acid while stirring at 0 to 90°C, and the precipitated crystals are collected by vacuum filtration and thoroughly washed with water. After drying,
Recrystallization from dimethylformamide 160+I11 yields 4-[α-hydroxy-2-methyl-5-(]-imidazolyl)benzyl]-3.5- as white needles.
14.0 g of dimethylbenzoic acid are obtained. Melting point 310
~312°C (decomposed).

Example 1 3.0 g of 4-(2-methoxy-5-(1-imidazolyl)benzoyl)-3,5-dimethylbenzoic acid and 0.4 g of sodium hydroxide were dissolved in 15+ wl of water, and borohydride was added to the solution. Add 0.66g of sodium, 70-7
The reaction is carried out under stirring at 5° C. for 3 hours. After the reaction is complete, remove a small amount of insoluble matter by filtration while still warm, adjust the pH of the filtrate to 4 with concentrated hydrochloric acid while stirring at 80-90°C, collect precipitated crystals by filtration under reduced pressure, and thoroughly wash with water. . After washing with acetone and drying, 4-[α-hydroxy-2
-methoxy-5-(1-imidazolyl)benzylco-3
, 2.7 g of 5-dimethylbenzoic acid are obtained.

Melting point 271-273°C (decomposed).

Example 2 6.4 g of 4-(2-chloro-5-(1-imidazolyl)benzoyl)-3,5-dimethylbenzoic acid and 0.8 g of sodium hydroxide were dissolved in water 35-1, and hydrogenated. Add 1.4 g of sodium boron and carry out the reaction at 70-75° C. for 3 hours with stirring. After the reaction, a small amount of insoluble matter was filtered off while still warm, the filtrate was stirred at 80 to 90°C, and the pH was adjusted to 4 with concentrated hydrochloric acid, and the precipitated crystals were collected by vacuum filtration, water,
After sequential washing with acetone and drying, white crystals of 4-[
6.1 g of α-hydroxy-2-chloro-5-(1-imidazolyl)benzyl)-3,5-dimethylbenzoic acid are obtained. Melting point 317-320°C (decomposition).

Example 3 A suspension consisting of 21 g of 4-(α-hydroxy-2-chloro-5-iodobenzoyl)-3,5-dimethylbenzoic acid, 5.1 g of imidazole, 13.8 g of potassium carbonate, and 120 g of dimethylformamide, Add 0.4g of potassium fluoride and 0.4g of copper powder to 135-140
The reaction is carried out under stirring at .degree. C. for 30 hours. After cooling, add 240 ml of water, and add 0 ml of sodium sulfide trihydrate.
．． Add 45 g and continue stirring for 30 minutes. The precipitated copper sulfide is filtered off under reduced pressure using Celite, the pH of the filtrate is adjusted to 4 with concentrated hydrochloric acid while heating and stirring, and the precipitated crystals are collected by filtration, washed with water, and then dried. When this was recrystallized from dimethylformamide, 4-[α-hydroxy-2-chloro-5-(1-imidazolyl)benzyl)-3,5-dimethylbenzoic acid was obtained in high yield as white needle crystals. It will be done. Melting point 318-320°C (decomposed).

Example 4 4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3.5-dimethylbenzoic acid 7.4
g is suspended in 80 ml of dimethylformamide, 4.5 g of triethylamine and 3.6 g of ethyl bromide are added thereto, and the mixture is stirred at room temperature for 7.5 hours. After the reaction is complete, pour into ice water and extract the precipitated crystals with ethyl acetate. The Ia layer is separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated. Recrystallizing the remainder from acetonitrile yields 4-
[Ethyl α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl)-3,5-dimethylbenzoate6.
5 g are obtained as white crystals. Melting point: 118-119°C When the crystals obtained above are converted into a hydrochloride with ethanolic hydrochloric acid in ethanol, 4-[α-hydroxy-2
-methyl-5-(1-imidazolyl)benzyl]-3.
Ethyl 5-dimethylbenzoate hydrochloride is obtained as white needles. Melting point 241-243°C (decomposition).

Example 5 2 g of 4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl)-3,5-dimethylbenzoic acid was suspended in 30 ml of dimethylformamide, and 1.2 g of triethylamine and isopropyl bromide were suspended in 30 ml of dimethylformamide. Add 1.1 g and stir at room temperature for 6.5 hours. After leaving it at room temperature overnight,
Pour into ice water and extract the precipitate with toluene. The toluene layer is separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue is recrystallized from acetonitrile to obtain 1.8 g of isopropyl 4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl)-3,5-dimethylbenzoate as white crystals. Melting point 19
3-194℃.

Example 6 4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl]-3.5-dimethylbenzoic acid 1.7
g was suspended in 10 ml of methanol and 20 ml of chloroform, and an ether solution of diazomethane was added dropwise while stirring.

After stirring at room temperature for 30 minutes, the solvent was distilled off and recrystallized from a small amount of toluene to give 4-[α-hydroxy-2-methyl-5-(1-imidazolyl)benzyl)-3,5-dimethylbenzoic acid. Methyl is obtained in quantitative yield as white crystals. Melting point 168-169°C.

Claims (1)

[Claims] An imidazole derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ or a pharmaceutically acceptable salt thereof and/or a hydrate thereof. In the formula, X represents halogen, lower alkyl, or lower alkoxy, and R represents hydrogen or lower alkyl. However, when X is lower alkyl, R represents lower alkyl.